Freeman–Sheldon syndrome

The symptoms of Freeman–Sheldon syndrome include drooping of the upper eyelids, strabismus, low-set ears, a long philtrum, gradual hearing loss, scoliosis and walking difficulties. Gastroesophageal reflux has been noted during infancy, but usually improves with age. The tongue may be small, and the limited movement of the soft palate may cause nasal speech. Often there is an H- or Y-shaped dimpling of the skin over the chin.{{citation needed|date=October 2020}}

FSS is caused by genetic changes. Krakowiak et al. (1998) mapped the distal arthrogryposis multiplex congenita (DA2B; MIM #601680) gene, a syndrome very similar in phenotypic expression to classic FSS, to 11p15.5-pter.{{cite journal |vauthors=Krakowiak PA, O'Quinn JR, Bohnsack JF |title=A variant of Freeman-Sheldon syndrome maps to 11p15.5-pter |journal=Am. J. Hum. Genet. |volume=60 |issue=2 |pages=426–32 |year=1997 |pmid=9012416 |pmc=1712403 |display-authors=etal}}{{cite journal |vauthors=Krakowiak PA, Bohnsack JF, Carey JC, Bamshad M |title=Clinical analysis of a variant of Freeman-Sheldon syndrome (DA2B) |journal=Am. J. Med. Genet. |volume=76 |issue=1 |pages=93–8 |year=1998 |pmid=9508073|doi=10.1002/(SICI)1096-8628(19980226)76:1<93::AID-AJMG17>3.0.CO;2-K}} Other mutations have been found as well.{{cite journal |vauthors=Sung SS, Brassington AM, Krakowiak PA, Carey JC, Jorde LB, Bamshad M |title=Mutations in TNNT3 cause multiple congenital contractures: a second locus for distal arthrogryposis type 2B |journal=Am. J. Hum. Genet. |volume=73 |issue=1 |pages=212–4 |year=2003 |pmid=12865991 |pmc=1180583 |doi=10.1086/376418 }}{{cite journal |vauthors=Sung SS, Brassington AM, Grannatt K |title=Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes |journal=Am. J. Hum. Genet. |volume=72 |issue=3 |pages=681–90 |year=2003 |pmid=12592607 |pmc=1180243 |doi=10.1086/368294 |display-authors=etal}} In FSS, inheritance may be either autosomal dominant, most often demonstrated.{{cite journal |vauthors=Aalam M, Kühhirt M |title=[Windmill vane-like finger deformities] |language=de |journal=Z Orthop Ihre Grenzgeb |volume=110 |issue=3 |pages=395–8 |year=1972 |pmid=4263226 }}{{cite journal |author=Jorgenson RJ |title=M--craniocarpotarsal dystrophy (whistling face syndrome) in two families |journal=Birth Defects Orig. Artic. Ser. |volume=10 |issue=5 |pages=237–42 |year=1974 |pmid=4220006 }}{{cite journal |vauthors=Wettstein A, Buchinger G, Braun A, von Bazan UB |title=A family with whistling-face-syndrome |journal=Hum. Genet. |volume=55 |issue=2 |pages=177–89 |year=1980 |pmid=7450762 |doi=10.1007/BF00291765|s2cid=8059018 }} or autosomal recessive (MIM 277720).{{cite journal |vauthors=Kousseff BG, McConnachie P, Hadro TA |title=Autosomal recessive type of whistling face syndrome in twins |journal=Pediatrics |volume=69 |issue=3 |pages=328–31 |year=1982 |doi=10.1542/peds.69.3.328 |pmid=7199706 |s2cid=245095688 }}{{cite journal |author=Kaul KK |title=Whistling face syndrome (craniocarpotarsal dysplasia) |journal=Indian Pediatr |volume=18 |issue=1 |pages=72–3 |year=1981 |pmid=7262998 }}{{cite journal |vauthors=Guzzanti V, Toniolo RM, Lembo A |title=[The Freeman-Sheldon syndrome] |language=it |journal=Arch Putti Chir Organi Mov |volume=38 |issue=1 |pages=215–22 |year=1990 |pmid=2136374 }}{{cite journal |vauthors=Sánchez JM, Kaminker CP |title=New evidence for genetic heterogeneity of the Freeman-Sheldon syndrome |journal=Am. J. Med. Genet. |volume=25 |issue=3 |pages=507–11 |year=1986 |pmid=3789012 |doi=10.1002/ajmg.1320250312}} Alves and Azevedo (1977) note most reported cases of DA2A have been identified as new allelic variation.{{cite journal |vauthors=Alves AF, Azevedo ES |title=Recessive form of Freeman-Sheldon's syndrome or 'whistling face' |journal=J. Med. Genet. |volume=14 |issue=2 |pages=139–41 |year=1977 |pmid=856233 |pmc=1013533 |doi=10.1136/jmg.14.2.139}} Toydemir et al. (2006) showed that mutations in embryonic myosin heavy chain 3 (MYH3; MIM *160270), at 17p-13.1-pter, caused classic FSS phenotype, in their screening of 28 (21 sporadic and 7 familial) probands with distal arthrogryposis type 2A.{{cite journal |vauthors=Toydemir RM, Rutherford A, Whitby FG, Jorde LB, Carey JC, Bamshad MJ |title=Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome |journal=Nat. Genet. |volume=38 |issue=5 |pages=561–5 |year=2006 |pmid=16642020 |doi=10.1038/ng1775|s2cid=8226091 }}{{OMIM|160720|MYOSIN, HEAVY CHAIN 3, SKELETAL MUSCLE, EMBRYONIC; MYH3}}

b .0001 c .0002 d .0004 e .0006, .0003 In 20 patients (12 and 8 probands, respectively), missense mutations (R672H; MIM *160270.0001 and R672C; MIM *160270.0002) caused substitution of arg672, an embryonic myosin residue retained post-embryonically. Of the remaining 6 patients in whom they found mutations, 3 had missense private de novo (E498G; MIM *160270.0006 and Y583S) or familial mutations (V825D; MIM *160270.0004); 3 other patients with sporadic expression had de novo mutations (T178I; MIM *160270.0003), which was also found in DA2B; 2 patients had no recognized mutations.

Freeman–Sheldon syndrome is a type of distal arthrogryposis, related to distal arthrogryposis type 1 (DA1).{{cite journal |vauthors=Hall JG, Reed SD, Greene G |title=The distal arthrogryposes: delineation of new entities—review and nosologic discussion |journal=Am. J. Med. Genet. |volume=11 |issue=2 |pages=185–239 |date=February 1982 |pmid=7039311 |doi=10.1002/ajmg.1320110208 }} In 1996, more strict criteria for the diagnosis of Freeman–Sheldon syndrome were drawn up, assigning Freeman–Sheldon syndrome as distal arthrogryposis type 2A (DA2A).

On the whole, DA1 is the least severe; DA2B is more severe with additional features that respond less favourably to therapy. DA2A (Freeman–Sheldon syndrome) is the most severe of the three, with more abnormalities and greater resistance to therapy.

Freeman–Sheldon syndrome has been described as a type of congenital myopathy.{{cite journal |vauthors=Vanĕk J, Janda J, Amblerová V, Losan F |title=Freeman-Sheldon syndrome: a disorder of congenital myopathic origin? |journal=J. Med. Genet. |volume=23 |issue=3 |pages=231–6 |date=June 1986 |pmid=3723551 |pmc=1049633 |doi= 10.1136/jmg.23.3.231}}

In March 2006, Stevenson et al. published strict diagnostic criteria for distal arthrogryposis type 2A (DA2A) or Freeman–Sheldon syndrome. These included two or more features of distal arthrogryposis: microstomia, whistling-face, nasolabial creases, and 'H-shaped' chin dimple.

Patients must have early consultation with craniofacial and orthopaedic surgeons, when craniofacial,{{cite journal |vauthors=Vaitiekaitis AS, Hornstein L, Neale HW |title=A new surgical procedure for correction of lip deformity in cranio-carpo-tarsal dysplasia (whistling face syndrome) |journal=J Oral Surg |volume=37 |issue=9 |pages=669–72 |date=September 1979 |pmid=288890 }}{{cite journal |author=Nara T |title=Reconstruction of an upper lip and the coloboma in the nasal ala accompanying with Freeman-Sheldon syndrome |journal=Nippon Geka Hokan |volume=50 |issue=4 |pages=626–32 |date=July 1981 |pmid=7316645 }}{{cite journal |vauthors=Ferreira LM, Minami E, Andrews Jde M |title=Freeman-Sheldon syndrome: surgical correction of microstomia |journal=Br J Plast Surg |volume=47 |issue=3 |pages=201–2 |date=April 1994 |pmid=8193861 |doi= 10.1016/0007-1226(94)90056-6}} clubfoot,{{cite journal |vauthors=Malkawi H, Tarawneh M |title=The whistling face syndrome, or craniocarpotarsal dysplasia. Report of two cases in a father and son and review of the literature |journal=J Pediatr Orthop |volume=3 |issue=3 |pages=364–9 |date=July 1983 |pmid=6874936 |doi= 10.1097/01241398-198307000-00017|s2cid=22025528 }} or hand correction{{cite journal |vauthors=Call WH, Strickland JW |title=Functional hand reconstruction in the whistling-face syndrome |journal=J Hand Surg Am |volume=6 |issue=2 |pages=148–51 |date=March 1981 |pmid=7229290 |doi= 10.1016/s0363-5023(81)80168-2}}{{cite journal |vauthors=Martini AK, Banniza von Bazan U |title=[Hand deformities in Freeman-Sheldon syndrome and their surgical treatment] |language=de |journal=Z Orthop Ihre Grenzgeb |volume=121 |issue=5 |pages=623–9 |year=1983 |pmid=6649810 |doi= 10.1055/s-2008-1053288}}{{cite journal |vauthors=Martini AK, Banniza von Bazan U |title=[Surgical treatment of the hand deformity in Freeman-Sheldon syndrome] |language=de |journal=Handchir Mikrochir Plast Chir |volume=14 |issue=4 |pages=210–2 |date=December 1982 |pmid=6763591 }}{{cite journal |vauthors=Wenner SM, Shalvoy RM |title=Two-stage correction of thumb adduction contracture in Freeman-Sheldon syndrome (craniocarpotarsal dysplasia) |journal=J Hand Surg Am |volume=14 |issue=6 |pages=937–40 |date=November 1989 |pmid=2584652 |doi= 10.1016/S0363-5023(89)80040-1}} is indicated to improve function or aesthetics. Operative measures should be pursued cautiously, with avoidance of radical measures and careful consideration of the abnormal muscle physiology in Freeman–Sheldon syndrome. Unfortunately, many surgical procedures have suboptimal outcomes, secondary to the myopathy of the syndrome.{{citation needed|date=November 2020}}

When operative measures are to be undertaken, they should be planned for as early in life as is feasible, in consideration of the tendency for fragile health. Early interventions hold the possibility to minimise developmental delays and negate the necessity of relearning basic functions.{{citation needed|date=October 2020}}

Due to the abnormal muscle physiology in Freeman–Sheldon syndrome, therapeutic measures may have unfavourable outcomes.{{cite journal |vauthors=Aldinger G, Eulert J |title=[The Freeman-Sheldon Syndrome] |language=de |journal=Z Orthop Ihre Grenzgeb |volume=121 |issue=5 |pages=630–3 |year=1983 |pmid=6649811 |doi=10.1055/s-2008-1053289}} Difficult endotracheal intubations and vein access complicate operative decisions in many DA2A patients, and malignant hyperthermia (MH) may affect individuals with FSS, as well.{{cite journal |vauthors=Laishley RS, Roy WL |title=Freeman-Sheldon syndrome: report of three cases and the anaesthetic implications |journal=Can Anaesth Soc J |volume=33 |issue=3 Pt 1 |pages=388–93 |year=1986 |pmid=3719442 |doi=10.1007/BF03010755|doi-access=free }}{{cite journal |vauthors=Munro HM, Butler PJ, Washington EJ |title=Freeman-Sheldon (whistling face) syndrome. Anaesthetic and airway management |journal=Paediatr Anaesth |volume=7 |issue=4 |pages=345–8 |year=1997 |pmid=9243695 |doi=10.1046/j.1460-9592.1997.d01-90.x|s2cid=40852324 }}{{cite journal |vauthors=Yamamoto S, Osuga T, Okada M |title=[Anesthetic management of a patient with Freeman-Sheldon syndrome] |language=ja |journal=Masui |volume=43 |issue=11 |pages=1748–53 |year=1994 |pmid=7861610 |display-authors=etal}}{{cite journal |vauthors=Sobrado CG, Ribera M, Martí M, Erdocia J, Rodríguez R |title=[Freeman-Sheldon syndrome: generalized muscular rigidity after anesthetic induction] |language=es|journal=Rev Esp Anestesiol Reanim |volume=41 |issue=3 |pages=182–4 |year=1994 |pmid=8059048 }} Cruickshanks et al. (1999) reports uneventful use of non-MH-triggering agents.{{cite journal |vauthors=Cruickshanks GF, Brown S, Chitayat D |title=Anesthesia for Freeman-Sheldon syndrome using a laryngeal mask airway |journal=Can J Anaesth |volume=46 |issue=8 |pages=783–7 |year=1999 |pmid=10451140 |doi=10.1007/BF03013916|doi-access=free }} Reports have been published about spina bifida occulta in anaesthesia management{{cite journal |vauthors=Namiki M, Kawamata T, Yamakage M, Matsuno A, Namiki A |title=[Anesthetic management of a patient with Freeman-Sheldon syndrome] |language=ja |journal=Masui |volume=49 |issue=8 |pages=901–2 |year=2000 |pmid=10998888 }} and cervical kyphoscoliosis in intubations.{{cite journal |vauthors=Vas L, Naregal P |title=Anaesthetic management of a patient with Freeman Sheldon syndrome |journal=Paediatr Anaesth |volume=8 |issue=2 |pages=175–7 |year=1998 |pmid=9549749 |doi=10.1046/j.1460-9592.1998.00676.x |s2cid=37359095 }}

General health maintenance should be the therapeutic emphasis in Freeman–Sheldon syndrome. The focus is on limiting exposure to infectious diseases because the musculoskeletal abnormalities make recovery from routine infections much more difficult in FSS. Pneumonitis and bronchitis often follow seemingly mild upper respiratory tract infections. Though respiratory challenges and complications faced by a patient with FSS can be numerous, the syndrome's primary involvement is limited to the musculoskeletal systems, and satisfactory quality and length of life can be expected with proper care.{{citation needed|date=October 2020}}

There are little data on prognosis. Rarely, some patients have died in infancy from respiratory failure; otherwise, life expectancy is considered to be normal.{{citation needed|date=November 2020}}

By 1990, 65 patients had been reported in the literature, with no sex or ethnic preference notable.{{cite encyclopedia | title = Freeman-Sheldon syndrome | encyclopedia = Orphanet Encyclopedia | publisher = Comier-Daire }} Some individuals present with minimal malformation; rarely patients have died during infancy as a result of severe central nervous system involvement{{cite journal |vauthors=Zampino G, Conti G, Balducci F, Moschini M, Macchiaiolo M, Mastroiacovo P |title=Severe form of Freeman-Sheldon syndrome associated with brain anomalies and hearing loss |journal=Am. J. Med. Genet. |volume=62 |issue=3 |pages=293–6 |date=March 1996 |pmid=8882790 |doi=10.1002/(SICI)1096-8628(19960329)62:3<293::AID-AJMG17>3.0.CO;2-F }} or respiratory complications.{{cite journal |vauthors=Rao SS, Chary R, Karan S |title=Freeman Sheldon syndrome in a newborn (whistling face)--a case report |journal=Indian Pediatr |volume=16 |issue=3 |pages=291–2 |date=March 1979 |pmid=110675 }} Several syndromes are related to the Freeman–Sheldon syndrome spectrum, but more information is required before undertaking such nosological delineation.{{cite journal |vauthors=Fitzsimmons JS, Zaldua V, Chrispin AR |title=Genetic heterogeneity in the Freeman-Sheldon syndrome: two adults with probable autosomal recessive inheritance |journal=J. Med. Genet. |volume=21 |issue=5 |pages=364–8 |date=October 1984 |pmid=6502650 |pmc=1049318 |doi= 10.1136/jmg.21.5.364}}{{cite journal |author=Träger D |title=[Cranio-carpo-tarsal dysplasia syndrome (Freeman-Sheldon syndrome, whistling face syndrome)] |language=de |journal=Z Orthop Ihre Grenzgeb |volume=125 |issue=1 |pages=106–7 |year=1987 |pmid=3577337 |doi= 10.1055/s-2008-1039687}}{{cite journal |vauthors=Simosa V, Penchaszadeh VB, Bustos T |title=A new syndrome with distinct facial and auricular malformations and dominant inheritance |journal=Am. J. Med. Genet. |volume=32 |issue=2 |pages=184–6 |date=February 1989 |pmid=2929657 |doi=10.1002/ajmg.1320320209 }}

One research priority is to determine the role and nature of malignant hyperthermia in FSS. Such knowledge would benefit possible surgical candidates and the anaesthesiology and surgical teams who would care for them. MH may also be triggered by stress in patients with muscular dystrophies.{{cite journal |vauthors=Litman RS, Rosenberg H |title=Malignant hyperthermia: update on susceptibility testing |journal=JAMA |volume=293 |issue=23 |pages=2918–24 |year=2005 |pmid=15956637 |doi=10.1001/jama.293.23.2918 }} Much more research is warranted to evaluate this apparent relationship of idiopathic hyperpyrexia, MH, and stress. Further research is wanted to determine epidemiology of psychopathology in FSS and refine therapy protocols.{{citation needed|date=October 2020}}

It is named for British orthopaedic surgeon Ernest Arthur Freeman (1900–1975) and British physician Joseph Harold Sheldon (1893–1972), who first described it in 1938.{{rp|577}}

Melissa Blake (writer) is a writer and disability advocate with Freeman-Sheldon syndrome.{{Cite book |last=Blake |first=Melissa |title=Beautiful people: my thirteen truths about disability |publisher=Hachette Go |year=2024 |isbn=978-0-306-83042-6 |edition= |location=New York City |language=English}}

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{{Medical resources

| DiseasesDB = 31817

| ICD10 =

| ICD9 = {{ICD9|759.89}}

| ICDO =

| OMIM = 193700

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| Orphanet = 2053

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Category:Syndromes affecting the tongue

Category:Genodermatoses

Category:Rare syndromes

Category:Syndromes with scoliosis

Category:Syndromes affecting the eye

Category:Syndromes with craniofacial abnormalities